Innate immunity of an organism is the in born protection against invading pathogens. Innate immune receptors sense components of invading organisms and trigger immune and inflammatory responses to combat infectious agents. In this proposal we intend to target three human innate immune receptors which among others are involved in detecting virus infection. We will use high throughput screening to identify chemical and small interfering RNA modifiers, which will specifically modulate Toll-like Receptor 3, Retinoic acid Inducible gene I and Toll-like receptor 7 signaling pathways. During the course of this investigation, we would like to find efficient modifiers, test their specificity, and make them available to the research community. We have successfully developed and used high throughput screening experiments to target one of the innate immune receptor - Toll-like Receptor 3. Using a cell-based readout system to screen for inhibitors we have identified novel signaling pathways involved in TLR3 mediated IRF3 activation and cytokine induction. In this proposal we will collaborate with University of Pittsburgh Drug Discovery Institute (DDI) to take advantage of the high throughput screening and drug development expertise of DDI to expand our screening efforts. This project will not only generate novel reagents for studying innate immune receptor signaling pathways, but may also provide building blocks for future drug development, which can be used to treat inflammatory diseases caused by virus infection. RELEVANCE: Innate immune receptors are the first line of sensors to recognize various components of invading pathogens and trigger immune and inflammatory responses to combat the infectious agent. We propose to target a few of these receptors which are involved in sensing virus infections, and identify novel reagents capable of modulating the functions of these receptors. Our long-term goal is to use these specific reagents to treat inflammatory and auto-immune diseases, which are caused by over or under-action of these receptors.